title: ZP2307, a novel, cyclic PTH(1-17) analog that augments bone mass in ovariectomized rats.
abstract: Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac₅c¹, Aib³, Leu⁸, Gln¹⁰, Har¹¹, Ala¹², Trp¹⁴, Asp¹⁷]PTH(1-17)-NH₂), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K¹³-D¹⁷ side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40-320 nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical testing of rat femora confirmed that ZP2307 dramatically increased bone strength. Over a broad maximally effective dose range (40-160 nmol/kg) ZP2307 did not increase serum concentrations of ionized free calcium above normal levels. Only at the highest dose (320 nmol/kg) ZP2307 induced hypercalcemic calcium levels in the ovariectomized rats. To our knowledge ZP2307 is the smallest PTH peptide analog known to exert augmentation of bone. Our findings suggest that ZP2307 has the potential to effectively augment bone mass over a broad dose range without a concomitant increase in the serum concentration of ionized free calcium above the normal range.
authors.affiliation: Zealand Pharma A/S, Smedeland 26B, 2600 Glostrup, Denmark. tsn@zealandpharma.com
authors.forename: Trine S R
authors.initials: TS
authors.lastname: Neerup
authors.forename: Martin
authors.initials: M
authors.lastname: Stahlhut
authors.forename: Jørgen S
authors.initials: JS
authors.lastname: Petersen
authors.forename: Jens R
authors.initials: JR
authors.lastname: Daugaard
authors.forename: Jens-Erik B
authors.initials: JE
authors.lastname: Jensen
authors.forename: Zhiqi
authors.initials: Z
authors.lastname: Peng
authors.forename: Jukka
authors.initials: J
authors.lastname: Morko
authors.forename: Christian
authors.initials: C
authors.lastname: Thorkildsen
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects*; D002118:Calcium / Q000097:blood; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D009929:Organ Size / Q000187:drug effects*; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D014057:Tomography, X-Ray Computed
chemical_list: D050071:Bone Density Conservation Agents; D010281:Parathyroid Hormone; D010446:Peptide Fragments; C561202:ZP2307; D000242:Cyclic AMP; D002118:Calcium